Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide

ABSTRACT

Disclosed are methods for preparing compounds of Formula 1 and 1A. The first method utilizes a benzyl carbamate amine protecting group and an intermediate of Formula 4. The second method utilizes a tert-butyl carbamate amine protecting group and an intermediate of Formula 7. The third method utilizes a dibenzyl amine protecting group. Also disclosed is a compound, phenylmethyl N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamate (a compound of Formula 4). Further disclosed is a method for preparing a compound of Formula 14 from a compound of Formula 15 and a compound of Formula 1 or 1A.

FIELD OF THE INVENTION

This invention pertains to a method for preparing2-amino-N-(2,2,2-trifluoroethyl)acetamide and its salts. The presentinvention also relates to intermediates for the aforedescribed methodand use of the subject compound as a starting material in otherpreparative methods.

SUMMARY OF THE INVENTION

The present invention provides a method for preparing a compound ofFormula 1

comprising (A) contacting a compound of Formula 2

with a compound of Formula 3

and a coupling reagent to form an intermediate of Formula 4 in thepresence of a base

(B) contacting the intermediate of Formula 4 with hydrogen in thepresence of a hydrogenolysis catalyst to give a compound of Formula 1,and (C) optionally contacting the compound of Formula 1 with an acid ofFormula 5

HX  5

-   -   wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3)        to provide the compound of Formula 1 in HX salt form (i.e.        Formula 1A).

The present invention also relates to novel compound phenylmethylN-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamate (a compound ofFormula 4) useful as an intermediate for the aforedescribed method.

The present invention also provides a method for preparing a compound ofFormula 1A

-   -   wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3).        comprising (A1) contacting a compound of Formula 8

with a compound of Formula 3

and a coupling reagent to form an intermediate of Formula 7 in thepresence of a base

and (B 1) contacting the intermediate of Formula 7 with an acid ofFormula 5

HX.  5

The invention also provides a method for preparing a compound of Formula14

comprising contacting a compound of Formula 15

with a compound of Formula 1 or 1A

-   -   wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3)        and a coupling reagent in the presence of a base.

DETAILS OF THE INVENTION

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having,” “contains” or “containing,” or any othervariation thereof, are intended to cover a non-exclusive inclusion. Forexample, a composition, a mixture, process, method, article, orapparatus that comprises a list of elements is not necessarily limitedto only those elements but may include other elements not expresslylisted or inherent to such composition, mixture, process, method,article, or apparatus. Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example,a condition A or B is satisfied by any one of the following: A is true(or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

Also, the indefinite articles “a” and “an” preceding an element orcomponent of the invention are intended to be nonrestrictive regardingthe number of instances (i.e. occurrences) of the element or component.Therefore “a” or “an” should be read to include one or at least one, andthe singular word form of the element or component also includes theplural unless the number is obviously meant to be singular.

The term “coupling reagent” refers to a reagent used to activate acarboxylic acid functional group to facilitate its condensation with anamine functional group to form an amide bond.

A compound of Formula 1 in HX salt form is a compound of Formula 1A

wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3).

The compound of Formula 1A is meant to represent a salt of the compoundof Formula 1 and it can be alternatively depicted as Formula 1AA shownbelow:

wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3).

When the X is indicated to be (SO₄)_(1/2) it is meant sulfuric acidforms a sulfate salt with the compound of Formula 1 as shown below;wherein the two structures correspond respectively to Formula 1AA andFormula 1A.

A compound of Formula 1 is 2-amino-N-(2,2,2-trifluoroethyl)acetamide. Acompound of Formula 1A is 2-amino-N-(2,2,2-trifluoroethyl)acetamidehydrochloride. A compound of Formula 4 is phenylmethylN-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamate. A compound ofFormula 14 is4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalene-carboxamide.

Embodiments of the present invention include:

-   -   Embodiment 1.0. The method described in step (A) of the Summary        of the Invention wherein the compounds of Formulae 2 and 3 and        the coupling reagent are contacted in the presence of a base and        a water immiscible solvent.    -   Embodiment 1.1. The method of Embodiment 1.0 wherein the water        immiscible solvent comprises ethyl acetate or iso-propyl        acetate.    -   Embodiment 1.2. The method of Embodiment 1.1 wherein the water        immiscible solvent comprises ethyl acetate.    -   Embodiment 1.3. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.3        wherein the coupling reagent comprises iso-butyl chloroformate        or N,N′-carbonyldiimidazole.    -   Embodiment 1.4. The method of Embodiment 1.3 wherein the        coupling reagent comprises N,N′-carbonyldiimidazole.    -   Embodiment 1.5. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.4        wherein the base comprises a basic reagent other than a compound        derived from the coupling reagent.    -   Embodiment 1.6. The method of Embodiment 1.5 wherein the basic        reagent comprises triethylamine or N,N-diisopropylethylamine.    -   Embodiment 1.7. The method of Embodiment 1.6 wherein the basic        reagent comprises triethylamine.    -   Embodiment 1.8. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.7        wherein the base is derived from the coupling reagent and the        coupling reagent is N,N′-carbonyldiimidazole.    -   Embodiment 1.9. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.8        wherein the compound of Formula 2 is first contacted with the        coupling reagent to form a mixture (i.e. containing the acyl        imidazole of Formula 6) and then the compound of Formula 3 is        added to the mixture in the presence of base.    -   Embodiment 1.10. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.9        wherein the mixture is at a temperature of at least about 15° C.    -   Embodiment 1.11. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.10        wherein the mixture is at a temperature of no more than about        40° C.    -   Embodiment 1.12. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.11        wherein the molar ratio of the coupling reagent to the compound        of Formula 2 is about 1.0 to about 1.1.    -   Embodiment 1.13. The method described in step (A) of the Summary        of the Invention or any one of Embodiments 1.0 through 1.12        wherein the molar ratio of the compound of Formula 3 to the        compound of Formula 2 is about 1.0.    -   Embodiment 1.14. The method described in step (B) of the Summary        of the Invention wherein the compound of Formulae 4 and hydrogen        are contacted in the presence of a hydrogenolysis catalyst and a        water immiscible solvent.    -   Embodiment 1.15. The method of Embodiment 1.14 wherein the water        immiscible solvent comprises ethyl acetate or iso-propyl        acetate.    -   Embodiment 1.16. The method of Embodiment 1.15 wherein the water        immiscible solvent comprises ethyl acetate.    -   Embodiment 1.17. The method described in step (B) of the Summary        of the Invention or any one of Embodiments 1.14 through 1.16        wherein the hydrogenolysis catalyst is a precious metal catalyst        or a supported precious metal catalyst.    -   Embodiment 1.18. The method of Embodiment 1.17 wherein the        hydrogenolysis catalyst is palladium on carbon.    -   Embodiment 1.19. The method of Embodiment 1.18 wherein the        hydrogenolysis catalyst is 5% or 10% palladium on carbon.    -   Embodiment 1.20. The method described in step (B) of the Summary        of the Invention or any one of Embodiments 1.14 through 1.19        wherein the hydrogenolysis is carried out at ambient        temperature.    -   Embodiment 1.21. The method described in step (B) of the Summary        of the Invention or any one of Embodiments 1.14 through 1.20        wherein the hydrogenolysis is carried out at a pressure of        atmospheric pressure to about 50 psi.    -   Embodiment 1.22. The method of Embodiment 1.21 wherein the        hydrogenolysis is carried out at atmospheric pressure.    -   Embodiment 1.23. The method described in step (C) of the Summary        of the Invention wherein the compound of Formula 1 is contacted        with an acid of Formula 5 in the presence of a water immiscible        solvent.    -   Embodiment 1.24. The method of Embodiment 1.23 wherein the water        immiscible solvent comprises ethyl acetate or iso-propyl        acetate.    -   Embodiment 1.25. The method of Embodiment 1.24 wherein the water        immiscible solvent comprises ethyl acetate.    -   Embodiment 1.26. The method described in step (C) of the Summary        of the Invention or any one of Embodiments 1.23 through 1.25        wherein the acid of Formula 5 comprises hydrogen chloride,        hydrogen bromide, trifluoroacetic acid, sulfuric acid, methane        sulfonic acid or phosphoric acid.    -   Embodiment 1.27. The method of Embodiment 1.26 wherein the acid        of Formula 5 comprises hydrogen chloride, hydrogen bromide and        sulfuric acid.    -   Embodiment 1.28. The method of Embodiment 1.27 wherein the acid        of Formula 5 comprises hydrogen chloride.    -   Embodiment 1.29. The method of Embodiment 1.28 wherein the        hydrogen chloride is in aqueous solution (i.e. hydrochloric        acid).    -   Embodiment 1.30. The method of Embodiment 1.28 wherein the        hydrogen chloride is anhydrous (i.e. hydrogen chloride gas).    -   Embodiment 1.31. The method described in step (C) of the Summary        of the Invention or any one of Embodiments 1.23 through 1.30        wherein the mixture is at a temperature of at least about 20° C.    -   Embodiment 1.32. The method described in step (C) of the Summary        of the Invention or any one of Embodiments 1.23 through 1.31        wherein the mixture is at a temperature of no more than about        45° C.    -   Embodiment 1.33. The method described in step (C) of the Summary        of the Invention or any one of Embodiments 1.23 through 1.32        wherein the molar ratio of the compound of Formula 1 to the acid        of Formula 5 is at least about 1.0.    -   Embodiment 1.34. The method described in step (C) of the Summary        of the Invention or any one of Embodiments 1.23 through 1.33        wherein the molar ratio of the compound of Formula 1 to the acid        of Formula 5 is no more than about 5.0.    -   Embodiment 2.0. The method described in step (A1) of the Summary        of the Invention wherein the compounds of Formulae 8 and 3 and        the coupling reagent are contacted in the presence of a base and        a water immiscible solvent.    -   Embodiment 2.1. The method of Embodiment 2.0 wherein the water        immiscible solvent comprises ethyl acetate or iso-propyl        acetate.    -   Embodiment 2.2. The method of Embodiment 2.1 wherein the water        immiscible solvent comprises ethyl acetate.    -   Embodiment 2.3. The method described in step (A1) of the Summary        of the Invention or any one of Embodiments 2.0 through 2.2        wherein the compound of Formula 8 is first contacted with the        coupling reagent to form a mixture (i.e. containing the acyl        imidazole of Formula 9) and then the compound of Formula 3 is        added to the mixture.    -   Embodiment 2.4. The method described in step (A1) of the Summary        of the Invention or any one of Embodiments 2.0 through 2.3        wherein the coupling reagent comprises iso-butyl chloroformate        or N,N′-carbonyldiimidazole.    -   Embodiment 2.5. The method of Embodiment 2.4 wherein the        coupling reagent comprises N,N′-carbonyldiimidazole.    -   Embodiment 2.6. The method described in step (A1) of the Summary        of the Invention or any one of Embodiments 2.0 through 2.5        wherein the base comprises a basic reagent other than a compound        derived from the coupling reagent.    -   Embodiment 2.7. The method of Embodiment 2.6 wherein the basic        reagent comprises triethylamine or N,N-diisopropylethylamine.    -   Embodiment 2.8. The method of Embodiment 2.7 wherein the basic        reagent comprises triethylamine.    -   Embodiment 2.9. The method described in step (A1) of the Summary        of the Invention or any one of Embodiments 2.0 through 2.8        wherein the base is derived from the coupling reagent and the        coupling reagent is N,N′-carbonyldiimidazole.    -   Embodiment 2.10. The method described in step (A1) of the        Summary of the Invention or any one of Embodiments 2.0 through        2.9 wherein the compound of Formula 8 is first contacted with        the coupling reagent to form a mixture and then the compound of        Formula 3 is added to the mixture in the presence of base.    -   Embodiment 2.11. The method described in step (A1) of the        Summary of the Invention or any one of Embodiments 2.0 through        2.10 wherein the mixture is at a temperature of at least about        15° C.    -   Embodiment 2.12. The method described in step (A1) of the        Summary of the Invention or any one of Embodiments 2.0 through        2.11 wherein the mixture is at a temperature of no more than        about 40° C.    -   Embodiment 2.13. The method described in step (A1) of the        Summary of the Invention or any one of Embodiments 2.0 through        2.12 wherein the molar ratio of the coupling reagent to the        compound of Formula 8 is about 1.0.    -   Embodiment 2.14. The method described in step (A1) of the        Summary of the Invention or any one of Embodiments 2.0 through        2.13 wherein the molar ratio of the compound of Formula 3 to the        compound of Formula 8 is about 1.0.    -   Embodiment 2.15. The method described in step (B 1) of the        Summary of the Invention wherein the compounds of Formulae 7 and        5 are contacted in the presence of a water immiscible solvent.    -   Embodiment 2.16. The method of Embodiment 2.15 wherein the water        immiscible solvent comprises ethyl acetate or iso-propyl        acetate.    -   Embodiment 2.17. The method of Embodiment 2.16 wherein the water        immiscible solvent comprises ethyl acetate.    -   Embodiment 2.18. The method described in step (B 1) of the        Summary of the Invention or any one of Embodiments 2.15 through        2.17 wherein the acid of Formula 5 comprises hydrogen chloride,        hydrogen bromide, trifluoroacetic acid, sulfuric acid, methane        sulfonic acid or phosphoric acid.    -   Embodiment 2.19. The method of Embodiment 2.18 wherein the acid        of Formula 5 comprises hydrogen chloride, hydrogen bromide and        sulfuric acid.    -   Embodiment 2.20. The method of Embodiment 2.19 wherein the acid        of Formula 5 comprises hydrogen chloride.    -   Embodiment 2.21. The method of Embodiment 2.20 wherein the        hydrogen chloride is in aqueous solution (i.e. hydrochloric        acid).    -   Embodiment 2.22. The method of Embodiment 2.20 wherein the        hydrogen chloride is anhydrous (i.e. hydrogen chloride gas).    -   Embodiment 2.23. The method described in step (B1) of the        Summary of the Invention or any one of Embodiments 2.15 through        2.22 wherein the mixture is at a temperature of at least about        20° C.    -   Embodiment 2.24. The method described in step (B 1) of the        Summary of the Invention or any one of Embodiments 2.15 through        2.23 wherein the mixture is at a temperature of no more than        about 45° C.    -   Embodiment 2.25. The method described in step (B 1) of the        Summary of the Invention or any one of Embodiments 2.15 through        2.24 wherein the molar ratio of the compound of Formula 7 to the        acid of Formula 5 is at least about 1.0.    -   Embodiment 2.26. The method described in step (B 1) of the        Summary of the Invention or any one of Embodiments 2.15 through        2.25 wherein the molar ratio of the compound of Formula 7 to the        acid of Formula 5 is no more than about 5.0.    -   Embodiment 3.0. The method described in the Summary of the        Invention for preparing the compound of Formula 14 wherein the        compounds of Formulae 1 or 1A and Formula 15 and the coupling        reagent are contacted in the presence of a base and a polar        aprotic water miscible solvent.    -   Embodiment 3.1. The method of Embodiment 3.0 wherein the polar        aprotic water miscible solvent comprises acetonitrile,        tetrahydrofuran or dioxane.    -   Embodiment 3.2. The method of Embodiment 3.1 wherein the polar        aprotic water miscible solvent comprises acetonitrile.    -   Embodiment 3.3. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.2 wherein the coupling reagent        comprises iso-butyl chloroformate or N,N′-carbonyldiimidazole.    -   Embodiment 3.4. The method of Embodiment 3.3 wherein the        coupling reagent comprises N,N′-carbonyldiimidazole.    -   Embodiment 3.5. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.4 wherein the base comprises a basic        reagent other than a compound derived from the coupling reagent.    -   Embodiment 3.6. The method of Embodiment 3.5 wherein the basic        reagent comprises triethylamine or N,N-diisopropylethylamine.    -   Embodiment 3.7. The method of Embodiment 3.6 wherein the basic        reagent comprises triethylamine.    -   Embodiment 3.8. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.7 wherein the base is derived from the        coupling reagent and the coupling reagent is        N,N′-carbonyldiimidazole.    -   Embodiment 3.9. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.8 wherein the compound of Formula 15        is first contacted with the coupling reagent to form a mixture        (i.e. containing the acyl imidazole of Formula 16) and then the        compound of Formula 1 or 1A is added to the mixture in the        presence of base.    -   Embodiment 3.10. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.9 wherein the compound of Formula 1 or        1A is added to the mixture as a solid or a solution in the polar        aprotic water miscible solvent.    -   Embodiment 3.11. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.10 wherein the compound of Formula 1        or 1A is added to the mixture as a solution or slurry in water.    -   Embodiment 3.12. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.12 wherein the mixture is at a        temperature of at least about 20° C.    -   Embodiment 3.13. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.12 wherein the mixture is at a        temperature of no more than about 45° C.    -   Embodiment 3.14. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.13 wherein the molar ratio of the        coupling reagent to the compound of Formula 15 is about 1.0 to        about 1.1.    -   Embodiment 3.15. The method described in the Summary of the        Invention for preparing the compound of Formula 14 or any one of        Embodiments 3.0 through 3.14 wherein the molar ratio of the        compound of Formula 1 or 1A to the compound of Formula 15 is        about 1.0.

Embodiments of this invention, including Embodiments 1.0-3.15 above aswell as any other embodiments described herein, can be combined in anymanner, and the descriptions of variables in the embodiments pertain notonly to the aforedescribed methods for preparing compounds of Formulae1, 1A and 14 but also to the starting compounds and intermediatecompounds useful for preparing the compounds of Formulae 1, 1A and 14 bythese methods.

In the following Schemes 1-9 the definition of X in the compounds ofFormulae 1 through 16 are as defined above in the Summary of theInvention and description of Embodiments unless otherwise indicated.

In the method of the invention, a benzyl carbamate (CBZ) amineprotecting group is used in the preparation of a compound of Formula 1as shown in Schemes 1 and 2. The compound of Formula 1 can be furtherreacted with acid to form the acid salt of Formula 1A as shown in Scheme3 (see synthesis Examples 1 and 2).

Step B of the method of the invention involves removal of the benzylcarbamate protecting group in an intermediate of Formula 4 viahydrogenolysis to give the free amine compound of Formula 1 as shown inScheme 1.

Removal of benzyl carbamate protecting groups can be accomplished with avariety of reaction conditions. See, for example, Greene, T. W.; Wuts,P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: NewYork, 1991. One particularly useful method for removal of the benzylprotecting group is via hydrogenolysis with hydrogen, usually underatmospheric pressure. Precious metal catalysts or supported preciousmetal catalysts are commonly used. Hydrogenolysis can also beaccomplished by hydrogen transfer with a supported precious metalcatalyst and a hydrogen donor (i e ammonium formate or cyclohexadiene).These methods are described in Rylander, P. N.; Hydrogenation Methods,Academic Press: San Diego, 1985. One particularly useful catalyst forthe hydrogenolysis is palladium on carbon (usually 5-10%). This methodis described in Harada et al., Bioorganic and Medicinal Chemistry 2001,9, 2709-2726 and Janda et al., Synthetic Communications 1990, 20,1073-1082. The benzyl carbamate protecting group can also be removedwith acid as described in Lesk et al., Synthetic Communications 1999,28, 1405-1408.

The method of Scheme 1 can be conducted over a range of temperatures.Typically the reaction temperature is at least about 20° C. or ambienttemperature. The hydrogenation can be conducted over a range ofpressures. Typically the hydrogenation is conducted at atmosphericpressure using a hydrogen balloon. The time needed for reaction isusually between 2 and 24 hours depending on the scale of the reaction.

In the present method the reaction mixture comprises a water immisciblesolvent. Solvents that have been found to be particularly useful areethyl acetate and iso-propyl acetate. Polar aprotic solvents that arewater immiscible are particularly useful because of their ability todissolve the starting material of Formula 4. The amount of solvent usedis the volume needed to dissolve the starting material, usually in therange of 0.5 to 1.0 molar concentration. The mixture of the startingmaterial and solvent can be warmed to about 30° C. to aid thedissolution of the compound of Formula 4 and enable the concentration ofthe reaction mixture to be greater than 0.5 molar.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the product is separated from the catalystby filtration. The resultant solution contains the free amine compoundof Formula 1. This solution can be concentrated to isolate the compoundof Formula 1. Alternatively the solution can be further reacted withacid as in Scheme 3 to make the compound of Formula 1A. Anotheralternative is adding water to the filtered solution wherein thecompound of Formula 1 will partition into the water and form an aqueoussolution which can be separated and used in subsequent reactions.

Step A of the method of the invention is the reaction of benzylcarbamate protected starting material of Formula 2 with a compound ofFormula 3 to give the intermediate of Formula 4 is shown in Scheme 2.Step A involves first activation of the carboxylic acid functional groupof the compound of Formula 2 with the coupling reagent to form an acylimidazole compound of Formula 6. The acyl imidazole intermediate ofFormula 6 can be isolated, but most of time it is not isolated andinstead is treated directly with the amine of Formula 3 to form an amidebond to give the compound of Formula 4.

A variety of coupling reagents can be used in to prepare the compound ofFormula 4. Several alkyl chloroformates and carbonyl diheteroarylreagents have been discovered to be particularly efficacious inproviding high yields of compounds of Formula 6. These coupling reagentsinclude methyl chloroformate, ethyl chloroformate, iso-butylchloroformate N,N′-carbonyldiimidazole and1,1′-carbonylbis(3-methylimidazolium)triflate, withN,N′-carbonyldiimidazole (also referred to as carbonyldiimidazole)preferred. N,N′-carbonyldiimidazole (shown in Scheme 2) is the mostefficient coupling reagent because it provides one equivalent of base toneutralize the amine salt of Formula 3. Chloroformate ester couplingreagents require the addition of a basic reagent to neutralize the acidgenerated from the reaction with a compound of Formula 2 and to liberatethe free base of the compound of Formula 3. An especially useful basefor this reaction is triethylamine.

The stoichiometry of this reaction involves equimolar amounts of thecompound of Formula 2 and the coupling reagent and the base. WhenN,N′-carbonyldiimidazole is the coupling reagent, one equivalent ofcarbon dioxide is evolved during formation of the acyl imidazoleintermediate (compound of Formula 6). An equivalent of imidazole is alsoreleased during formation of the acyl imidazole and it reacts with oneequivalent of hydrogen chloride when the amine salt of Formula 3 isadded to the reaction mixture. Therefore, the base can be derived fromthe coupling reagent when the coupling reagent isN,N′-carbonyldiimidazole. An equivalent of additional base (basicreagent not derived from the coupling reagent) like triethylamine isoptional when N,N′-carbonyldiimidazole is the coupling reagent.Additional base (for example triethylamine or diisopropylethylamine)will speed the reaction since it is more basic than imidazole and reactsfaster with the hydrogen chloride salt of Formula 3 to release its freebase form for reaction with the acyl imidazole. The molar ratio of thecoupling reagent to the compound of Formula 2 can range from about 0.95to about 1.15 however a ratio of at least 1.0 is preferred to ensurecomplete formation of the acyl imidazole intermediate of Formula 6.

The stoichiometry of the reaction further involves equimolar amounts ofthe compound of Formula 3 and the compound of Formula 2. The molar ratioof the compound of Formula 3 to the compound of Formula 2 can range fromabout 1.0 to about 1.15 however a ratio of at least 1.05 is preferred toensure complete reaction of the acyl imidazole intermediate with thecompound of Formula 3.

The order of addition of the reactants in step A of the method of theinvention is very important. The compound of Formula 2 can be dissolvedin the solvent and the coupling reagent added to it or the couplingreagent can be dissolved in the solvent and the compound of Formula 2added to it. However, it is important to give the acyl imidazoleformation enough time before the addition of the compound of Formula 3.The acyl imidazole formation can usually be monitored by evolution ofcarbon dioxide gas over 1 to 2 hours depending on the scale of thereaction.

The compounds of Formula 2 and Formula 3 are commercially available. Thecompound of Formula 3 is particularly preferred because of its ease inhandling. Trifluoroethyl amine can be used in its neutral state but itis volatile (boiling point 36-37° C.) and less convenient.

In the present method the reaction mixture comprises a water immisciblesolvent. Solvents that have been found to be particularly useful areethyl acetate and iso-propyl acetate. Polar aprotic solvents that arewater immiscible are particularly useful because of their ability todissolve the starting material of Formula 2 and can be separated fromwater in an aqueous workup. The amount of solvent used is the volumeneeded to dissolve the starting material, usually in the range of 0.75to 1.5 molar concentration with 1.0 molar concentration beingparticularly useful.

The reaction of the method of Scheme 2 can be conducted over a widerange of temperatures. Typically the reaction temperature is at leastabout 15° C. and most typically at least about 20° C. Typically thereaction temperature is no more than about 40° C. and most typically nomore than about 35° C.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the mixture is typically worked up byaddition of an aqueous mineral acid such as hydrochloric acid.Separation of the organic phase, further washing with hydrochloric acid(1.0 N) to remove imidazole (and any optional triethylamine that wasadded), drying over desiccants such as magnesium sulfate or molecularsieves, or azeotropic drying and then evaporation of the solvent leavesthe product of Formula 4, as a colorless solid. Evaporation of thesolvent is optional; when azeotropic drying is employed the solvent isnot removed and a solution of a compound of Formula 4 is carriedforward.

Step C of the method of the invention is optional and involves thereaction of the free amine of Formula 1 with an acid of Formula 5 togive the acid salt of Formula 1A as shown in Scheme 3.

wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3).

The free amine of Formula 1 is sensitive to air. The resultant solution(from step B) of the compound of Formula 1 can be treated with acid toproduce the more stable acid salt of Formula 1A. The compound of Formula1A is then isolated by filtration and dried in a vacuum oven (50-60° C.)or air dried. The salt of Formula 1A can be stored at ambient conditionswithout the deleterious effects from weight gain from moisture and airexposure and handling problems from a hygroscopic sticky texture. SeeExample 12 for comparison of the compounds of Formula 1 and 1A and othersalts.

Non-aqueous acids of Formula 5 have been discovered to be particularlyefficacious in providing high yields of compounds of Formula 1A. Theseacids include hydrogen chloride, hydrogen bromide, trifluoroacetic acid,methane sulfonic acid, sulfuric acid or phosphoric acid with hydrogenchloride preferred for its low cost. The acid is usually bubbled intothe catalyst free reaction mixture or in the case of liquid acids addeddropwise. The non-aqueous acids of Formula 5 are added to the waterimmiscible solvent solution from step B to give the solid salt ofFormula 1A that can be easily isolated by filtration. Alternativelyaqueous acids of Formula 5 (for example concentrated hydrochloric acid)can be added dropwise to the solution of Formula 1 from step B to givean aqueous phase containing the compound of Formula 1A. This aqueousphase can be separated from the water immiscible solvent and used insubsequent reactions.

An alternative to the benzyl carbamate (CBZ) amine protecting group usedin the method of the invention in Schemes 1 and 2 is the tert-butylcarbamate (BOC) amine protecting group shown in Schemes 4 and 5 (seesynthesis Examples 3 and 4).

In step B of the method of the invention illustrated in Scheme 4, acompound of Formula 1A is directly prepared by contacting a compound ofFormula 7 with an acid of Formula 5. The reaction involves both removalof a tert-butyl carbamate protecting group and simultaneous formation ofthe salt of an amine functional group.

wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3).

The stoichiometry of this reaction involves equimolar amounts of theacid of Formula 5 relative to the compound of Formula 7. However, amolar excess of about 2.0 to about 5.0 of the acid of Formula 5 isdesirable to ensure complete removal of the tert-butyl carbamateprotecting group from the compound of Formula 7 and complete formationof the acid salt of Formula 1A.

Non-aqueous acids of Formula 5 have been discovered to be particularlyefficacious in providing high yields of compounds of Formula 1A. Theseacids include hydrogen chloride, hydrogen bromide, trifluoroacetic acid,methane sulfonic acid, sulfuric acid or phosphoric acid with hydrogenchloride preferred for its low cost. The anhydrous acids in the form ofa gas like hydrogen chloride (see synthesis Example 4 step B) areusually bubbled into the reaction mixture. In the case of liquid acidslike trifluoroacetic acid (see synthesis Example 7) the liquid is addeddropwise. The non-aqueous acids of Formula 5 are used in a waterimmiscible solvent to give a solid salt of Formula 1A that can be easilyisolated by filtration of the reaction mixture. Formation and isolationof the product salt using the above procedure avoids an aqueous workupstep. The isolated solid salt of Formula 1A can be used in subsequentreactions.

Aqueous acids of Formula 5 have been discovered to also be efficaciousin providing high yields of compounds of Formula 1A. These acids includehydrochloric acid and hydrobromic acid with hydrochloric acid preferredfor its low cost (see synthesis Example 4 Step B1). The aqueous acid isusually dripped into the reaction mixture. When the aqueous acids ofFormula 5 are used in a water immiscible solvent, the salt of Formula 1Ais formed and then dissolved in a water phase that separates from theorganic phase. The concentrated aqueous solution of the compound ofFormula 1A can be easily isolated by drawing off the more dense aqueousphase from the bottom of the reaction vessel. The concentrated aqueoussolution of the compound of Formula 1A can be used in subsequentreactions.

In the present method the reaction mixture comprises a water immisciblesolvent. Solvents that have been found to be particularly useful areethyl acetate and iso-propyl acetate. Polar aprotic solvents that arewater immiscible are particularly useful because of their ability todissolve the starting material of Formula 7 and cause the precipitationof the product of Formula 1A. The amount of solvent used is the volumeneeded to dissolve the starting material, usually in the range of 0.5 to1.0 molar concentration. The mixture of the starting material andsolvent can be warmed to about 30° C. to aid the dissolution of thecompound of Formula 7 and enable the concentration of the reactionmixture to be greater than 0.5 molar. Once the starting material isdissolved the heating source is removed and the acid is added to thereaction mixture at ambient temperature.

The method shown in Scheme 4 can be conducted over a wide range oftemperatures. Typically the reaction temperature is at least about 20°C. or ambient temperature. The reaction mixture usually warms during thereaction but the exotherm usually does not require external cooling andreaction temperature usually remains below the boiling point of thesolvent. Typically the reaction temperature is no more than about 45° C.and most typically no more than about 40° C.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the mixture is typically cooled to roomtemperature and the product isolated by conventional methods, such asfiltration. The solid product recovered by filtration can be dried in avacuum oven (50-60° C.) or air dried.

In step A of the method of the invention illustrated in Scheme 5, acompound of Formula 7 is prepared by contacting a compound of Formula 8with a compound of Formula 3 and a coupling reagent. The method toprepare a compound of Formula 7 involves first activation of thecarboxylic acid functional group of the compound of Formula 8 with thecoupling reagent to form an acyl imidazole compound of Formula 9. Theacyl imidazole compound of Formula 9 can be isolated, but is usually notisolated. It forms an amide bond with the amine functional group in thecompound of Formula 3 to give the compound of Formula 7.

The stoichiometry of this reaction involves equimolar amounts of thecompound of Formula 8 and the coupling reagent and the base. WhenN,N′-carbonyldiimidazole is the coupling reagent, one equivalent ofcarbon dioxide is evolved during formation of the acyl imidazoleintermediate (compound of Formula 9). An equivalent of imidazole is alsoreleased during formation of the acyl imidazole and it reacts with oneequivalent of hydrogen chloride when the amine salt of Formula 3 isadded to the reaction mixture. Therefore, the base can be derived fromthe coupling reagent when the coupling reagent isN,N′-carbonyldiimidazole. An equivalent of additional base (basicreagent not derived from the coupling reagent) like triethylamine isoptional when N,N′-carbonyldiimidazole is the coupling reagent.Additional base (for example triethylamine or diisopropylethylamine)will speed the reaction since it is more basic than imidazole and reactsfaster with the hydrogen chloride salt of Formula 3 to release its freebase form for reaction with the acyl imidazole. The molar ratio of thecoupling reagent to the compound of Formula 2 can range from about 0.95to about 1.15 however a ratio of at least 1.0 is preferred to ensurecomplete formation of the acyl imidazole intermediate of Formula 9. Thestoichiometry of the reaction involves equimolar amounts of the compoundof Formula 3 and the compound of Formula 8. The molar ratio of thecompound of Formula 3 to the compound of Formula 8 can range from about1.0 to about 1.15 however a ratio of at least 1.05 is preferred toensure complete reaction of the acyl imidazole intermediate with thecompound of Formula 3.

A variety of coupling reagents can be used for step A. Several alkylchloroformates and carbonyl diheteroaryl reagents have been discoveredto be particularly efficacious in providing high yields of compounds ofFormula 7. These coupling reagents include methyl chloroformate, ethylchloroformate, iso-butyl chloroformate N,N′-carbonyldiimidazole and1,1′-carbonylbis(3-methylimidazolium)triflate, withN,N′-carbonyldiimidazole (also referred to as carbonyldiimidazole)preferred. N,N′-carbonyldiimidazole is the most efficient couplingreagent because it provides one equivalent of base to neutralize theamine salt of Formula 3. Chloroformate ester coupling reagents requirethe addition of a basic reagent to neutralize the acid generated fromthe reaction with a compound of Formula 8 and to liberate the free baseof the compound of Formula 3 (see synthesis Example 6). An especiallyuseful base for this reaction is triethylamine.

The order of addition of the reactants in step A of the method of theinvention is very important. The compound of Formula 8 can be dissolvedin the solvent and the coupling reagent added to it or the couplingreagent can be dissolved in the solvent and the compound of Formula 8added to it. However, it is important to give the acyl imidazoleintermediate formation enough time before the addition of the compoundof Formula 3. The acyl imidazole intermediate formation can usually bemonitored by evolution of carbon dioxide gas over 1 to 2 hours dependingon the scale of the reaction.

The compounds of Formula 8 and Formula 3 are commercially available. Thecompound of Formula 3 is particularly preferred because of its ease inhandling. Trifluoroethyl amine can be used in its neutral state but itis volatile (boiling point 36-37° C.) and less convenient. A compound ofFormula 7 can also be prepared from commercially available N-BOC-glycineN-carboxyanhydride (see synthesis Example 5).

In the present method the reaction mixture comprises a water immisciblesolvent. Solvents that have been found to be particularly useful areethyl acetate and iso-propyl acetate. Polar aprotic solvents that arewater immiscible are particularly useful because of their ability todissolve the starting material of Formula 8 and can be separated fromwater in an aqueous workup. The amount of solvent used is the volumeneeded to dissolve the starting material, usually in the range of 0.75to 1.5 molar concentration with 1.0 molar concentration beingparticularly useful.

The reaction of the method of Scheme 5 can be conducted over a widerange of temperatures. Typically the reaction temperature is at leastabout 15° C. and most typically at least about 20° C. The reactionmixture usually warms during the reaction but the exotherm usually doesnot require external cooling and reaction temperature usually remainsbelow the boiling point of the solvent. Typically the reactiontemperature is no more than about 40° C. and most typically no more thanabout 35° C.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the mixture is typically worked up byaddition of a dilute aqueous mineral acid such as hydrochloric acid.Separation of the organic phase, further washing with hydrochloric acid(1.0 N) to remove imidazole or other added base, drying over desiccantssuch as magnesium sulfate or molecular sieves, or azeotropic drying andthen evaporation of the solvent leaves the compound of Formula 7, as acolorless solid. Evaporation of the solvent is optional; when azeotropicdrying is employed the solvent is not removed and a solution of acompound of Formula 7 is carried forward.

Another alternative to the benzyl carbamate (CBZ) amine protecting groupused in the method of the invention in Schemes 1 and 2 is the dibenzylamine protecting group shown in Schemes 6, 7 and 8 (see synthesisExample 8).

The dibenzyl amine alternative process involves removal of a dibenzylprotecting group in an intermediate of Formula 10 via hydrogenolysis togive the free amine compound of Formula 1 as shown in Scheme 6.

Removal of the benzyl protecting groups can be accomplished with avariety of reaction conditions. See, for example, Greene, T. W.; Wuts,P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: NewYork, 1991. One particularly useful method for removal of the benzylprotecting group on nitrogen is via hydrogenolysis with hydrogen usingprecious metal catalysts, usually under pressure. This method isdescribed in Rylander, P. N.; Hydrogenation Methods, Academic Press: SanDiego, 1985. One particularly useful catalyst for the hydrogenolysis ispalladium on carbon (5-10%).

Removal of benzyl protecting groups from nitrogen requires more vigorousconditions than removal of the benzyl protecting group from oxygen (asin the BOC procedure). The hydrogenolysis reaction is usually conductedunder pressure and at elevated temperature. A pressure of 50-100 psi ofhydrogen is typical. Typically the reaction temperature is 50 to 80° C.Temperatures in the range of about 70° C. are preferred. The reaction isnot exothermic and requires external heating to maintain the desiredtemperature

In the method of Scheme 6, the reaction mixture comprises an organicsolvent. Solvents that have been found to be particularly useful aremethanol and ethanol, other solvents typically used for hydrogenationcan also be used. The amount of organic solvent used is the volumeneeded to dissolve the starting material, usually in the range of 0.3 to1.0 molar concentration. The mixture of the starting material of Formula10 in the solvent is heated to the desired temperature under hydrogenpressure. The reaction is heated until the reaction is complete, asindicated by the cease of hydrogen uptake.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots, or byrate of hydrogen uptake. After completion of the reaction, the mixtureis typically cooled to ambient temperature and filtered to remove thesupported catalyst. The product compound of Formula 1 is isolated byconcentration and is recovered as an oil.

The compound of Formula 10 can be prepared by contacting a compound ofFormula 11 with a compound of Formula 12 in the presence of a base. Thealkylation of the amine of Formula 12 with the alkyl chloride of Formula11 is shown in Scheme 7.

The stoichiometry of this reaction involves equimolar amounts of thechloroacetyl amide of Formula 11 relative to the amine of Formula 12.However, a molar excess of about 1.1 to about 1.2 of the amine ofFormula 12 is desirable to ensure complete reaction of thechloroacetamide of Formula 11 and complete formation of the dibenzylamine of Formula 10. The reaction also requires an equimolar amount ofbase. Depending on the base used, a molar excess of up to 2.0equivalents may be required. The preferred base is a tertiary amine,such as triethylamine or Hunig's base (diisoproplyethylamine), butalkali metal carbonates can be used.

In the method shown in Scheme 7 the reaction mixture comprises anorganic solvent. A solvent that has been found to be particularly usefulis methanol, but aromatic solvents, such as toluene, or polar aproticsolvents, such as acetonitrile, can also be used. The amount of organicsolvent used is the volume needed to dissolve the starting materials,usually in the range of 0.5 to 1.0 molar concentration with 0.7 molarconcentration being particularly useful. The mixture of the startingchloroacetyl amide, dibenzylamine and base in the solvent are heated toreflux, or to higher temperatures by running under pressure.Temperatures in the range of 80 to 100° C. are preferred. The reactionis heated until the reaction is complete, typically 12 to 24 hours.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the mixture is typically cooled to ambienttemperature and concentrated to remove the solvent. The oil residue isdissolved in methylene chloride, or similar solvent, and washed at leasttwice with water. The product is isolated by conventional methods, suchas concentration. The oil product recovered by concentrationcrystallizes on cooling.

The starting material dibenzylamine (a compound of Formula 12) iscommercially available.

The compound of Formula 11 can be prepared by contacting a compound ofFormula 13 with a compound of Formula 3A in the presence of a base. Thereaction of the amine of Formula 3A with the acid chloride of Formula 13is shown in Scheme 8.

The stoichiometry of this reaction involves equimolar amounts of theacid chloride of Formula 13 relative to the amine of Formula 3A.However, a molar excess of about 1.05 to about 1.1 of the acid chlorideof Formula 13 is desirable to ensure complete reaction of the amine ofFormula 3A and complete formation of the product of Formula 11. Thereaction also requires and equimolar amount of base. A molar excesssimilar to the molar excess of acid chloride is advantageous. Thepreferred base is potassium carbonate, but a variety of alkali metalcarbonates or bicarbonates can be used.

In the method of Scheme 8 the reaction mixture comprises a two phasesystem of water and a water immiscible solvent. Solvents that have beenfound to be particularly useful are ethyl acetate and diethyl ether. Theamount of organic solvent used is the volume needed to dissolve thestarting materials, usually in the range of 1.0 to 1.5 molarconcentration for the amine and 4.0 to 5.0 molar for the acid chloride.The amount of water used is the volume needed to dissolve the alkalimetal carbonate base and varies according to the solubility of the basedused. With potassium carbonate a concentration range of 1.0 to 3.0 molarconcentration is typical. The mixture of the starting trifluoroethylamine (compound of Formula 3A) in solvent and the carbonate in water isagitated and cooled to about −5 to 0° C. The solution of thechloroacetyl chloride (compound of Formula 13) in the solvent is addedto the cooled reaction mixture over 0.5 to 2 hours while maintaining thetemperature at −5 to 0° C., then the reaction is stirred at thattemperature for 1 hour.

The reaction of the method of Scheme 8 can be conducted over a narrowrange of temperatures. Typically the reaction temperature is below 10°C. and most typically below 0° C. The reaction is exothermic andrequires external cooling to maintain the desired temperature.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the mixture is typically phase separated andthe solvent phase washed with water, and the product isolated byconcentration of the solvent. The oil product recovered by concentrationcrystallizes on standing.

The starting materials chloroacetyl chloride (compound of Formula 13)and trifluoroethyl amine (compound of Formula 3A) are commerciallyavailable.

In another aspect of the present invention, compounds of Formula 14 areprepared from compounds of Formula 1 or Formula 1A. In the method shownin Scheme 9, a compound of Formula 15 is contacted with a couplingreagent to form an intermediate of Formula 16. The acyl imidazoleintermediate of Formula 16 can be isolated (see synthesis Example 9).Most of time the acyl imidazole is not isolated and instead is treateddirectly with a compound of Formula 1 or 1A to form the compound ofFormula 14.

When N,N′-carbonyldiimidazole is the coupling reagent, one equivalent ofcarbon dioxide is evolved during formation of the acyl imidazoleintermediate (compound of Formula 16). An equivalent of imidazole isalso released during formation of the acyl imidazole and it reacts withone equivalent of acid (i.e. hydrogen chloride, hydrogen bromide,trifluoroacetic acid, methane sulfonic acid, sulfuric acid or phosphoricacid) when the amine salt of Formula 1A is added to the reactionmixture. Therefore, the base can be derived from the coupling reagentwhen the coupling reagent is N,N′-carbonyldiimidazole. An equivalent ofadditional base (basic reagent not derived from the coupling reagent)like triethylamine is optional when N,N′-carbonyldiimidazole is thecoupling reagent. Additional base (for example triethylamine ordiisopropylethylamine) will speed the reaction since it is more basicthan imidazole and reacts faster with the hydrogen chloride salt ofFormula 1A to release its free base form for reaction with the acylimidazole. Alternatively the acyl imidazole of Formula 16 can be reactedwith the free amine of Formula 1 instead of its acid salt of Formula 1A.No additional base is needed when the free amine of Formula 1 is used inthe preparation of the compound of Formula 14. See synthesis Example 10for reaction using a compound of Formula 1 and synthesis Example 11 forreaction using a compound of Formula 1A.

The stoichiometry of the reaction in Scheme 9 involves equimolar amountsof the compound of Formula 15 and the coupling reagent and the base. Themolar ratio of the coupling reagent to the compound of Formula 15 canrange from about 0.95 to about 1.15 however a ratio of about 0.97 ispreferred to maximize formation of the acyl imidazole intermediate ofFormula 16 without any excess N,N′-carbonyldiimidazole left over. Thestoichiometry of the reaction involves equimolar amounts of the compoundof Formula 1 or 1A and the compound of Formula 15. The molar ratio ofthe compound of Formula 1 or 1A to the compound of Formula 15 can rangefrom about 1.0 to about 1.15 however a ratio of at least 1.05 ispreferred to ensure complete reaction of the acyl imidazole intermediate(compound of Formula 16) with the compound of Formula 1 or 1A.

A variety of coupling reagents can be used in Scheme 9. Several alkylchloroformates and carbonyl diheteroaryl reagents have been discoveredto be particularly efficacious in providing high yields of compounds ofFormula 14. These coupling reagents include methyl chloroformate, ethylchloroformate, iso-butyl chloroformate N,N′-carbonyldiimidazole and1,1′-carbonylbis(3-methylimidazolium)triflate, withN,N′-carbonyldiimidazole (also referred to as carbonyldiimidazole)preferred. N,N′-carbonyldiimidazole is the most efficient couplingreagent because it provides one equivalent of base to neutralize theamine salt of Formula 1A. Chloroformate ester coupling reagents requirethe addition of a basic reagent to neutralize the acid generated fromthe reaction with a compound of Formula 15 and to liberate the free baseof the compound of Formula 3. An especially useful base for thisreaction is triethylamine.

The order of addition of the reactants is important. The couplingreagent is usually dissolved in the solvent and the compound of Formula15 added to it. It is important to give the acyl imidazole formationenough time before the addition of the compound of Formula 1 or 1A. Theacyl imidazole intermediate formation (compound of Formula 16) canusually be monitored by evolution of carbon dioxide gas over 0.5 to 2hours depending on the scale of the reaction.

The compound of Formula 1 or 1A is commercially available or is preparedby the method of the invention shown in previous Schemes. The compoundof Formula 1 or 1A can be added to the mixture as a solid or slurry in apolar aprotic water miscible solvent. The compound of Formula 15 wasprepared according to the procedure of F. Feist in Justus LiebigsAnnalen der Chemie 1932, 496, 99-122. The compound of Formula 1A isespecially useful because of its ease in handling since it is nothygroscopic (see Example 16). Use of the neutral free amine compound ofFormula 1 is less convenient because it is hygroscopic and exposure toair needs to minimized.

In the present method the reaction mixture comprises a water misciblepolar aprotic solvent. Solvents that have been found to be useful areacetonitrile, tetrahydrofuran and dioxane. Acetonitrile was found to beparticularly useful. The amount of solvent used is the volume needed todissolve the starting material, usually in the range of 0.75 to 1.5molar concentration with 1.0 molar concentration being particularlyuseful.

The method of Scheme 9 can be conducted over a wide range oftemperatures. Typically the reaction temperature is at least about 20°C. and most typically at least about 30° C. The reaction mixture usuallywarms during the reaction but the exotherm usually does not requireexternal cooling and reaction temperature usually remains below theboiling point of the solvent. Typically the reaction temperature is nomore than about 45° C. and most typically no more than about 35° C.

Reaction progress can be monitored by conventional methods such as thinlayer chromatography, GC, HPLC and ¹H NMR analyses of aliquots. Aftercompletion of the reaction, the mixture is typically worked up byaddition of an aqueous mineral acid such as hydrochloric acid (1.1 moleof 1N). The brief acid treatment is used to hydrolyze any imine thatmight be formed between the acetyl group on the product (compound ofFormula 14) and excess amine from the compound of Formula 1. Then, thepH is adjusted to 9-10 with base (sodium hydroxide or sodium carbonate)resulting in a slurry. The slurry is cooled to 20° C. and filtered. Theresultant solid product is washed with water and dried in a vacuum oven(50-60° C.).

An alternative procedure for the preparation of a compound of Formula 14uses an aqueous solution of a compound of Formula 1 or 1A. Remarkablywater can be tolerated in the reaction mixture with the acyl imidazoleintermediate of Formula 16. The acyl imidazole intermediate of Formula16 reacts faster with the more nucleophilic amine of Formula 1 (eitheradded directly or formed by neutralization of the hydrochloride salt ofFormula 1A) than with the less nucleophilic water introduced with theaqueous solution of Formula 1 or 1A.

This reaction to prepare the compound of Formula 14 using an aqueoussolution of a compound of Formula 1 or 1A is performed in a similarmanner to the procedure for using a compound of Formula 1 or 1A in thesolid form. The order of addition of the reactants is similar to thatdiscussed previously. When the acyl imidazole intermediate formation iscomplete, optionally a small quantity of water is added to hydrolyze anyexcess N,N′-carbonyldiimidazole (0.26 mole equivalent) and prevent sidereactions. After the water quench of excess N,N′-carbonyldiimidazole at20° C. for 1 hour, a concentrated aqueous solution of a compound ofFormula 1 or 1A (about 50 M) or a slurry of a compound of Formula 1 or1A in water is added dropwise. The reaction between the compound ofFormula 1 or 1A and the intermediate of Formula 16 in aqueousacetonitrile usually takes 12 to 24 hours to complete. See synthesisExamples 12, 13, 14 and 15.

The aqueous solution of a compound of Formula 1 or 1A is prepared byadding water to the dry solid or is directly prepared in the procedurediscussed below Scheme 1. The compound of Formula 15 was preparedaccording to the procedure of F. Feist in Justus Liebigs Annalen derChemie 1932, 496, 99-122.

Another alternative procedure for the preparation of a compound ofFormula 14 using the acid chloride of the compound of Formula 15 and thecompound of Formula 1 is described in Example 7 of WO 2009/025983.

Without further elaboration, it is believed that one skilled in the artusing the preceding description can utilize the present invention to itsfullest extent. The following Examples are, therefore, to be construedas merely illustrative, and not limiting of the disclosure in any waywhatsoever. Steps in the following Examples illustrate a procedure foreach step in an overall synthetic transformation, and the startingmaterial for each step may not have necessarily been prepared by aparticular preparative run whose procedure is described in otherExamples or Steps. Percentages are by weight except for chromatographicsolvent mixtures or where otherwise indicated. Parts and percentages forchromatographic solvent mixtures are by volume unless otherwiseindicated. ¹H NMR spectra are reported in ppm downfield fromtetramethylsilane; “s” means singlet, “d” means doublet, “t” meanstriplet, “q” means quartet, “m” means multiplet, “dd” means doublet ofdoublets, “dt” means doublet of triplets and “br” means broad.

Example 1 Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamidehydrochloride

N,N-Carbonyldiimidazole (8.2 g, 50.5 mmol) was added to a slurry ofN-[(phenylmethoxy)carbonyl]glycine (10 g, 47.8 mmol) in iso-propylacetate (100 mL) over 14 mins. The resulting solution was stirred forabout 1 hr and then triethylamine (4.84 g, 47.8 mmol) was added followedby portionwise addition of trifluoroethylamine hydrochloride (6.8 g,50.2 mmol) over 25 mins keeping the temperature below 30° C. The slurrywas treated with water (50 mL) and iso-propyl acetate (25 mL). Theresulting biphasic mixture was allowed to settle and the phases wereseparated. The aqueous layer was extracted with iso-propyl acetate (2×25mL). The combined organic phases were washed with 1 N hydrochloric acid(50 mL), water (50 mL), saturated aqueous sodium bicarbonate (50 mL),brine (50 mL) and then dried over sodium sulfate (25 g) overnight. Theslurry was filtered and the residue washed with iso-propyl acetate (30mL).

10% Palladium on carbon (1.00 g) was added to the combined wash andfiltrate and placed under a hydrogen atmosphere (balloon). Afterapproximately 2 hours, the reaction slurry was heated to 50° C. andhydrogenated for approximately 4 hours. The reaction mixture was placedunder a nitrogen atmosphere, cooled to room temperature and thenfiltered through a Celite® pad (15 g) wetted with iso-propyl acetate.The residue was rinsed with iso-propyl acetate (30 mL). The combinedfiltrate and rinse was treated with hydrogen chloride gas until the pHof the mixture was 1-2 by pH indicator paper, then nitrogen was bubbledthrough the slurry at 30-35° C. until the pH was 4-6 by pH indicatorpaper. The slurry was cooled to <5° C. and filtered. The residue wasrinsed with iso-propyl acetate (20 mL) and dried in a vacuum oven at 60°C. to give the title compound as a gray solid (7.75 g, 84% yield).

Example 2 Preparation of phenylmethylN-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamate

N,N-Carbonyldiimidazole (38.72 g, 0.2328 mol) was added to a slurry ofN-[(phenylmethoxy)carbonyl]glycine (50 g, 0.239 mol) in ethyl acetate(350 mL) over 5 mins. The resulting solution was stirred for 65 minutes,then trifluoroethylamine hydrochloride (32.9 g, 0.24 mol) was added inportions keeping the temperature at 22° C. The reaction mixture wasstirred for 17 hrs, then quenched with water (250 mL) and extracted withethyl acetate (150 mL). The resulting biphasic mixture was allowed tosettle and the phases were separated. The organic phase was washed twicewith 1 N hydrochloric acid (100 mL each) and dried over magnesiumsulfate (20 g) overnight. The slurry was filtered and the residue washedwith 4 portions of ethyl acetate (50 mL, 100 mL, 100 mL, 50 mL). Thewashes and the filtrate were combined and concentrated to a solid. Thesolid was dried in a vacuum oven at 40° C. to give the title compound asa white solid (54.1 g, 78% yield).

1H NMR (DMSO-d₆): 8.55 (tr, J=6.4 Hz, 1H), 7.53 (tr, J=6.1 Hz, 1H),7.43-7.22 (m, 5H), 5.04 (s, 2H), 4.01-3.79 (m, 2H), 3.68 ppm (d, J=6.1Hz, 2H); ¹⁹F-NMR (DMSO-d6): −70.76 ppm (tr, J=10.1 Hz).

Example 3 A Second Preparation of2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

A solution of tert.-butoxycarbonylglycine (285.7 g, 1.63 mol) in ethylacetate (1140 mL) was added over about 1 hr to a slurry ofN,N-carbonyldiimidazole (264.5 g, 1.63 mol) in ethyl acetate (570 mL) atambient temperature. The reaction mixture was stirred for 1 hour andthen 2,2,2-trifluoroethylamine hydrochloride (239.5 g, 1.77 mol) wasadded in portions over about 15 mins. The slurry was stirred for 5 hoursat ambient temperature and then 1 N hydrochloric acid (860 mL) is added.The biphasic mixture was allowed to settle, and the phases wereseparated. The organic phase was consecutively washed with 1Nhydrochloric acid (860 mL) and 5% sodium carbonate aqueous solution (860mL), and then dried over magnesium sulfate and filtered. The filter cakewas rinsed with ethyl acetate (200 mL). Hydrogen chloride gas (217 g,5.95 mol) was bubbled through the combined filtrates at 20 to 37° C.over 2 hours. The resulting slurry was sparged with nitrogen andfiltered. The residue was washed twice with ethyl acetate (500 mL each)and then dried in a vacuum oven at 60° C. to give the title compound asa white solid (235.5 g, 75% yield).

Example 4 A Third Preparation of2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride Step A:Preparation of N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamicacid 1,1-dimethylethyl ester

N,N-carbonyldiimidazole (8.87 g, 54.7 mmol) was added to a solution ofN-tert-butoxycarbonylglycine (19 g, 57.1 mmol) in anhydrous ethylacetate (50 ml) over 2 mins. The reaction mixture was stirred for 33mins, and then 2,2,2-trifluoroethylamine (5.1 mL, 63.5 mmol) was addedover 12 mins. The resulting solution was stirred overnight at ambienttemperature, and then quenched with 1 N hydrochloric acid (25 mL). Thereaction mixture was allowed to settle and the phases were separated.The organic phase was washed three times with water (25 ml each),diluted with ethyl acetate (10 mL), and dried over magnesium sulfate (5g) for several hours. The slurry was filtered and the residue washedthree times with ethyl acetate (10 mL). The filtrate and washes werecombined and concentrated in-vacuo to give a white solid (12.7 g).

1H NMR (DMSO-d₆): 8.44 (tr, J=6.5 Hz, 1H), 7.01 (tr, J=6.2 Hz, 1H),3.87-3.84 (m, 2H), 3.63-3.51 (d, J=6.4 Hz, 2H), 1.21-1.50 ppm (s, 9H);¹⁹F-NMR (DMSO-d6): −70.75 ppm (tr, J=10 Hz).

Step B: Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamidehydrochloride

A portion of the product of Example 2, Step A (11.7 g) was diluted withethyl acetate (50 mL) and treated with hydrogen chloride gas at 18-35.5°C. until the starting material was consumed. The resulting slurry wascooled to 0-5° C., stirred for approximately 1 hour at that temperature,and then filtered. The residue was washed twice with ethyl acetate (20ml each) and dried in a vacuum oven at 60° C. to give the title compoundas a white solid (7.22 g, 66% yield).

1H NMR (DMSO-d₆): 9.24 (tr, J=6.2 Hz, 1H), 8.3 (s, 3H), 4.11-3.89 (m,2H), 3.64 (s, 2H), 1.21-1.50 ppm (s, 9H); ¹⁹F-NMR (DMSO-d6): −70.69 ppm(tr, J=10.1 Hz).

Step B1 Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamidehydrochloride

Hydrochloric acid (37 wt %, 2.1 mL, 25.6 mmol) was added in two portionsto a mixture of N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamicacid 1,1-dimethylethyl ester (2.03 g, 7.9 mmol) in dichloromethane (10mL) and water (0.7 mL). The resulting mixture was stirred at ambienttemperature for about 2 hrs, then a solution of sodium carbonate (1.82g) in water (6 g) was added. The cloudy mixture was acidified with 1Nhydrochloric acid (21 mL) and diluted with 20 mL dichloromethane. Thephases were separated and the aqueous phase concentrated to dryness on arotary evaporator to give 3.16 g of the title compound as a white solid.

Example 5 Preparation ofN-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamic acid1,1-dimethylethyl ester

2,2,2-trifluoroethylamine (2.1 mL, 26.1 mmol) was added dropwise to aslurry of 2,5-dioxo-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester(5.01 g, 24.8 mmol) in ethyl acetate (25 mL) at 3-6° C. The reaction wasallowed to reach ambient temperature and stir overnight. The resultantslurry was diluted with ethyl acetate (35 mL) and washed successivelywith 5 wt % sodium carbonate (10 mL) and twice with water (10 mL each).The organic phase was dried over magnesium sulfate (5 g) and filteredvia Buchner funnel. The residue on the funnel was washed twice withethyl acetate (10 mL each) and the wash combined with the originalfiltrate. The combined organic phases were concentrated under vacuum anddried in a vacuum oven at 35° C. under a light nitrogen purge to givethe title compound as a white solid (5.76 g, 90.8% yield).

Example 6 A Fourth Preparation of2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

Triethylamine (11.67 g, 115 mmol) was added to a solution oftert.-butoxycarbonylglycine (20 g, 114 mol) in dichloromethane (110 mL)at <10° C. in one portion followed by addition of iso-butylchloroformate(15.75 g, 115 mmol) over 8 mins. The reaction mixture was allowed tostir for about 3.3 hrs at 10° C., then a solution of trifluoroethylamine(17 g, 171.6 mmol) and triethylamine (12.7 g, 122.5 mmol) indichloromethane (72 mL) was added dropwise over 7 mins. The reactionmixture was stirred for about 2 hrs then quenched with 1 N hydrochloricacid (60 mL). The biphasic mixture was allowed to settle, and the phaseswere separated. The organic phase was consecutively washed with 1 Nhydrochloric acid (60 mL) and 5% sodium carbonate aqueous solution (60mL), and then dried over sodium sulfate and filtered. The filter cakewas rinsed with ethyl acetate (30 mL) and the filtrate concentrated invacuo. Ethyl acetate (50 mL) was added to the residue and the solutionconcentrated to an oil (23.81 g). The residue was redissolved in ethylacetate (150 mL) and treated with hydrogen chloride gas at 35-41° C.until the GC analysis indicated completion of the deprotection reaction.The resulting slurry was sparged with nitrogen and filtered. The residuewas washed twice with ethyl acetate (20 mL each) and dried in a vacuumoven at 60° C. to give the title compound as a white solid (8.9 g, 41%yield).

Example 7 Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamidetrifluoroacetate

A solution of trifluoroacetic acid (4.8 mL, 61.7 mmol) indichloromethane (22 ml) was added to a slurry ofN-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]carbamic acid1,1-dimethylethyl ester (11.97 g, 46.7 mmol) in dichloromethane (50 mL)over 23 min at room temperature. The solution was heated to 39° C. andkept at that temperature for about 2 hrs. The solution was allowed tocool to ambient temperature then trifluoroacetic acid (4.8 mL, 61.7mmol) was added and the hazy reaction mixture allowed to stir overnight.The reaction mixture was cooled to 0-5° C., kept at that temperature for70 mins and then filtered via Büchner funnel to give a colorlessgelatinous residue. The residue was washed with dichloromethane (1×40mL, 1×15 mL) and then dried in a vacuum oven at 35° C. under a lightnitrogen purge to give the title compound as a white sticky solid (6.08g, 39.4%).

¹H NMR (DMSO-d₆): 9.13 (tr, J=6.3 Hz, 1H), 8.19 (s, 3H), 4.14-3.85 (m,2H), 3.68 (s, 2H), ¹⁹F-NMR (DMSO-d₆): −70.83 ppm (tr, J=10 Hz), −74.93(s).

Example 8 A Fifth Preparation of2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride Step A:Preparation of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide

A solution of chloroacetyl chloride (60.8 g, 0.52 mol) in ethyl acetate(120 mL) was added to a pre-cooled (−5 to 0° C.) biphasic mixture oftrifluoroethylamine (47.6 g, 0.48 mol) in anhydrous ethyl acetate (360mL) and potassium carbonate (33.2 g, 0.24 mol) in water (120 mL) over 35min. The reaction mixture was stirred for 60 min at that temperature.The reaction mixture was allowed to settle and the phases wereseparated. The organic phase was washed with water and concentratedunder vacuum to give an oil. Methanol was added to dissolve the oil andthe solution was concentrated under vacuum to a colorless oil whichcrystallized on cooling to a white solid (89.6 g).

¹H NMR (DMSO-d₆): 8.89 (bs, 1H), 4.17 (s, 2H), 3.91-3.99 (m, 2H).

Step B: Preparation of2-[bis(phenylmethyl)amino]-N-(2,2,2-trifluoroethyl)acetamide

A portion of the product of Example 7, Step A (40.0 g, 0.23 mol) wasdissolved in methanol (300 mL) and added to a pressure reactor (Parrmodel 4540, 600 mL, Hasteloy C) along with dibenzylamine (39.5 g, 0.19mol) and triethylamine (22.4 g, 0.22 mol). The reactor was flushed withnitrogen and sealed, then heated to 85° C. and held for 23 hours at thattemperature. The reactor was cooled to ambient temperature and the crudereaction product was concentrated under vacuum to a red viscous oilwhich was redissolved in methylene chloride (400 mL). The solution waswashed twice with water (450 mL total) and concentrated under vacuum toan amber oil which crystallized on cooling (63.5 g).

¹H NMR (DMSO-d₆): 8.38 (tr, 1H), 7.30-7.43 (m, 10H), 3.85-4.0 (m, 2H),3.63 (s, 4H), 3.07 (s, 2H).

Step C: Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamidehydrochloride

A portion of the product of Example 7, Step B (12.0 g) was dissolved inmethanol (300 mL) and added to a pressure reactor (Parr model 4540, 600mL, Hasteloy C) along with 5% palladium on carbon (0.6 g) catalyst. Thereactor was flushed with nitrogen and then with hydrogen, and heated to70° C. under 100 psi of hydrogen pressure until the hydrogen uptakeceased (3 hr). The reactor was cooled and flushed with nitrogen, thenthe crude reaction product was filtered through a bed a Celite® filteraid to remove the catalyst and the cake washed with methanol. Thesolvent and toluene by-product were removed by distillation, leaving anamber oil (5.45 g, 89% product by GC).

The crude oil product from two runs of the above hydrogenolysis (10.9 gtotal) was diluted with ethyl acetate (50 mL) and treated with hydrogenchloride gas at ambient temperature until the starting material wasconsumed. The resulting slurry was filtered and the solid was washedwith ethyl acetate (20 mL) and dried on the filter under a blanket ofnitrogen to give the title compound as a white solid (10.0 g).

¹H NMR (DMSO-d₆): 9.24 (tr, J=6.2 Hz, 1H), 8.3 (s, 3H), 4.11-3.89 (m,2H), 3.64 (s, 2H); ¹⁹F-NMR (DMSO-d6): −70.69 ppm (tr, J=10.1 Hz).

Example 9 Preparation of1-[4-(1H-imidazole1-ylcarbonyl)-1-naphthalenyl]ethanone

1H-Imidazole (1.17 g, 17.2 mmol) was added to a solution of4-acetyl-1-naphthalenecarbonylchloride (2.01 g, 8.6 mmol) indichloromethane (35 mL). The resulting slurry was stirred at ambienttemperature for 11.5 hrs then cooled to 0° C. with an ice/water bath.Cold water (35 mL) was added and the reaction mixture transferred to aseparatory funnel. The phases were separated, and the organic phase waswashed with water (35 mL) and dried over magnesium sulfate. The slurrywas filtered and the filtrate concentrated under vacuum to give thetitle compound as an orange oil.

¹H NMR (CDCl₃): 8.63-8.60 (m, 1H), 7.97-7.91 (m, 3H), 7.72-7.60 (m, 3H),7.51 (tr, 1H, J=1.4 Hz), 7.18-7.17 (m, 1H), 2.80 (s, 3H).

Example 10 Preparation of4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide

4-Acetyl-1-naphthalenecarboxylic acid (680 g, 3.14 mol) was added infive portions over 1 hour to a slurry of N,N-carbonyldiimidazole (505 g,3.11 mol) in anhydrous acetonitrile (2720 mL) at ambient temperature.The solution was stirred for 2.5 hrs and then warmed to 35° C.2-Amino-N-(2,2,2-trifluoroethyl)acetamide (530 g, 3.73 mol) was thenadded in five portions over 30 mins. The reaction mixture was allowed tostir for 2 hours at 35-40° C., then cooled and allowed to stir overnightat ambient temperature. The resulting slurry was treated with water(5540 mL) over 40 mins, followed by addition of a 1 N hydrochloric acidsolution (5440 mL) over 30 mins. The reaction mixture was cooled to 5°C., held at that temperature for 1 hour and then filtered. The residuewas washed 3 times with water (1360 mL each) and dried in a vacuum ovenat 60° C. under a nitrogen purge to give the title product as a whitesolid (1042.6 g, 88.8% yield).

¹H NMR (CD₃S(═O)CD₃): 8.95 (t, J=5.8 Hz, 1H), 8.72 (t, J=6.5 Hz, 1H),8.55 (dd, J=6.5, 2 Hz, 1H), 8.37-8.33 (m, 1H), 8.13 (d, J=7.3 Hz, 1H),7.70-7.60 (m, 3H), 4.07-3.95 (m, 4H), 2.75 (s, 3H).

Example 11 A Second Preparation of4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide

4-Acetyl-1-naphthalenecarboxylic acid (675 g, 3.15 mol) was added infive portions over 32 mins to a slurry of N,N-carbonyldiimidazole (486g, 3.00 mol) in anhydrous acetonitrile (2578 mL) at about 36° C. Thesolution was stirred for approximately 2 hrs at this temperature andthen 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (629 g,3.27 mol) was added in five portions over 36 mins. The reaction mixturewas allowed to stir overnight at 35° C. and then cooled to about 18° C.to initiate crystallization. The resulting slurry was warmed to 35° C.and then 1 N hydrochloric acid (3064 mL) was added over 90 mins,followed by addition of a solution of 50% sodium hydroxide (514.2 g) inwater (7356 mL) over 81 mins. The reaction mixture was cooled to about18° C., held at that temperature for 30 mins and then filtered Theresidue was washed 3 times with water (700 mL each) and dried in avacuum oven at 60° C. under a nitrogen purge to give the title productas a white solid (988.6 g, 87.7% yield).

Example 12 A Third Preparation of4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide

4-Acetyl-1-naphthalenecarboxylic acid (50 g, 0.2273 mol) was added inportions to a slurry of N,N-carbonyldiimidazole (39.76 g, 0.2388 mol) inanhydrous acetonitrile (200 mL) at 30° C. The solution was stirred for 2hrs at 30° C. and then cooled to 20° C. Water (1.06 g, 58.8 mmol) wasadded to the mixture and it was stirred for 1 hr. A solution of2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (45.98 g, 0.2388mol) in water (21.5 g) was then added over 1 hr at 19-20° C. Thereaction mixture was allowed to stir for 17 hours. To the resultingslurry, water (100 mL) was added, followed by addition of a solution ofsodium carbonate (24.1 g, 0.2274 mol) in water (350 mL) over 25 mins andwater (350 mL) over 22 mins The reaction mixture was stirred at 20-25°C. for 6.5 hrs and filtered. The residue was washed 3 times with water(100 mL each) and dried in a vacuum oven at 50-60° C. under a nitrogenpurge to give the title product as a white solid (72.3 g, 86.1% yield).

Example 13 A Fourth Preparation of4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide

Anhydrous acetonitrile (40 mL) was added to4-acetyl-1-naphthalenecarboxylic acid (10.0 g, 46.5 mmol) andN,N-carbonyldiimidazole (7.62 g, 46.5 mmol). The solution was stirredfor 5.75 hrs at 25° C., and then heated to 30° C. A solution of2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (9.84 g, 50.8mmol) in water (4.32 g) was added over 6 mins. The reaction mixture wasallowed to stir for 16.3 hours at 30° C. and then cooled to 20° C. Tothe resulting slurry, water (20 mL) was added, followed by addition of asolution of sodium carbonate (9.86 g, 93 mmol) in water (140 mL) overabout 1 hr. The reaction mixture was stirred at 20-25° C. overnight,held at 0-8° C. for 2.25 hrs and then filtered. The residue was washed 3times with water (20 mL each) and dried in a vacuum oven at 50° C. undera nitrogen purge to give the title product as an off-white solid (14.83g, 87.8% yield).

Example 14 A Fifth Preparation of4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide

4-Acetyl-1-naphthalenecarboxylic acid (10.0 g, 46.5 mmol) was added to aslurry of N,N-carbonyldiimidazole (8.21 g, 50.1 mmol) in anhydrousacetonitrile (40 mL). The solution was stirred for 1.3 hrs at ambienttemperature. Water (0.2 mL, 11.1 mmol) was added and the solutionstirred for 30 mins. A solution of2-amino-N-(2,2,2-trifluoroethyl)acetamide sulfate (11.25 g, 54.8 mmol)in water (22.6 g) was prepared and filtered to remove insolubles andthen added over 3 mins to the reaction mixture. The reaction mixture wasallowed to stir for 21.3 hrs at 21-23° C. To the resulting slurry, water(20 mL) was added, followed by addition of a solution of sodiumcarbonate (9.82 g, 92.7 mmol) in water (140 mL) over 15 minutes. Thereaction mixture was cooled and stirred at 0-5° C. for 2.3 hrs and thenfiltered. The residue was washed 3 times with water (20 mL each) anddried in a vacuum oven at 45° C. under a slight nitrogen purge to givethe title compound as an off-white solid (12.6 g, 76.9% yield).

Example 15 A Sixth Preparation of4-acetyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide

4-Acetyl-1-naphthalenecarboxylic acid (10.0 g, 46.5 mmol) was added to aslurry of N,N-carbonyldiimidazole (8.22 g, 50.2 mmol) in anhydrousacetonitrile (40 mL). The solution was stirred for 2 hrs 10 mins at 19to 21° C. Water (0.2 mL, 11.1 mmol) was added and the solution stirredfor 1 hr. A solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (9.03g, 55.1 mmol) in water (16.5 g) was prepared and filtered to removeinsolubles. The solid residue on the filter was washed with water (1.58g) and washings combined with the filtered aqueous solution of2-amino-N-(2,2,2-trifluoroethyl)acetamide. The aqueous solution of2-amino-N-(2,2,2-trifluoroethyl)acetamide was added to the reactionmixture containing the acylimidazole intermediate over 12 mins. Thereaction mixture was allowed to stir for 20.6 hours at ambienttemperature. To the resulting slurry, water (20 mL) was added, followedby dropwise addition of a solution of sodium carbonate (4.91 g, 46.3mmol) in water (70 mL) over 16 mins and water (70 mL) over 10 mins. Thereaction mixture was cooled and stirred at 2-7° C. for 2.5 hrs and thenfiltered. The residue was washed 3 times with water (20 mL each) anddried in a vacuum oven at 45° C. under a slight nitrogen purge to givethe title compound as an off-white solid (13.83 g, 84.4% yield).

Example 16 Stability comparison for free base and salts of2-amino-N-(2,2,2-trifluoroethyl)acetamide

The 2-amino-N-(2,2,2-trifluoroethyl)acetamide free base unexpectedlyshowed weight gain upon exposure to the ambient atmosphere, whereas thecorresponding hydrochloride salt did not. This result was not expectedas hydrochloride salts of amines are quite frequently hydroscopic. Tofurther characterize the stability of the free amine and salts of2-amino-N-(2,2,2-trifluoroethyl)acetamide the following experiments wereperformed. Samples of the free amine and salts were exposed to air inthe laboratory for a period of time. Weight lain or loss compared to theoriginal sample was determined

Time [days] in ambient Salt % Weight gain (loss) atmosphere Free base4.65 3 Hydrochloride (0.09) 2 Trifluoroacetate (0.22) 2.6Methanesulfonate (0.76) 5

What is claimed is:
 1. A method for preparing a compound of Formula 1

comprising (A) contacting a compound of Formula 2

with a compound of Formula 3

and a coupling reagent to form an intermediate of Formula 4 in thepresence of a base

(B) contacting the intermediate of Formula 4 with hydrogen in thepresence of a hydrogenolysis catalyst to give a compound of Formula 1,and (C) optionally contacting the compound of Formula 1 with an acid ofFormula 5HX  5 wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3) toprovide the compound of Formula 1 in HX salt form.
 2. The method ofclaim 1 step (A) wherein the compounds of Formulae 2 and 3 and thecoupling reagent are contacted in the presence of a base and a waterimmiscible solvent.
 3. The method of claim 2 wherein the base is derivedfrom the coupling reagent and the coupling reagent isN,N′-carbonyldiimidazole.
 4. The method of claim 1 step (B) wherein thecompound of Formulae 4 and hydrogen are contacted in the presence of ahydrogenolysis catalyst and a water immiscible solvent.
 5. The method ofclaim 4 wherein the hydrogenolysis catalyst is palladium on carbon. 6.The method of claim 1 step (C) wherein the compound of Formula 1 iscontacted with an acid of Formula 5 in the presence of a waterimmiscible solvent.
 7. The method of claim 6 wherein the acid of Formula5 comprises hydrogen chloride.
 8. (canceled)
 9. A compound which isphenylmethyl N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]-ethyl]carbamate.10. A method for preparing a compound of Formula 1A

wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3).comprising (A1) contacting a compound of Formula 8

with a compound of Formula 3

and a coupling reagent to form an intermediate of Formula 7 in thepresence of a base

and (B1) contacting the intermediate of Formula 7 with an acid ofFormula 5HX.  5
 11. The method of claim 10 step (A1) wherein the compounds ofFormulae 8 and 3 and the coupling reagent are contacted in the presenceof a base and a water immiscible solvent.
 12. The method of claim 11wherein the base is derived from the coupling reagent and the couplingreagent is N,N′-carbonyldiimidazole.
 13. The method of claim 10 step(B1) wherein the compounds of Formulae 7 and 5 are contacted in thepresence of a water immiscible solvent.
 14. The method of claim 13wherein the acid of Formula 5 comprises hydrogen chloride. 15.(canceled)
 16. A method for preparing a compound of Formula 14

comprising contacting a compound of Formula 15

with a compound of Formula 1 or 1A

wherein X is Cl, Br, CF₃CO₂, CH₃SO₃, (SO₄)_(1/2) or (PO₄)_(1/3) and acoupling reagent in the presence of a base.
 17. The method of claim 16wherein the compounds of Formulae 1 or 1A and Formula 15 and thecoupling reagent are contacted in the presence of a base and a polaraprotic water miscible solvent.
 18. The method of claim 17 wherein thepolar aprotic water miscible solvent comprises acetonitrile,tetrahydrofuran or dioxane.
 19. The method of claim 17 wherein the baseis derived from the coupling reagent and the coupling reagent isN,N′-carbonyldiimidazole.
 20. (canceled)
 21. (canceled)
 22. (canceled)